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Originally published as JCO Early Release 10.1200/JCO.2008.17.7725 on October 27 2008 © 2008 American Society of Clinical Oncology.
Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype
Sarcoma Unit, Royal Marsden Hospital, London, United Kingdom The introduction of the tyrosine kinase inhibitor imatinib has transformed the therapy of advanced or metastatic gastrointestinal stromal tumor (GIST).1,2 However, despite truly remarkable early results, it soon became apparent that this treatment did not result in cure but, rather, in a high objective response and disease stabilization rate. In the European Organisation for Research and Treatment of Cancer (EORTC) phase I study, 19 of 36 patients with GIST achieved a partial response, and 13 had minor responses or stable disease, which led to a clinical benefit rate of 89%.3 In the subsequent phase II study conducted at the maximum-tolerated dose (MTD) of imatinib 800 mg daily, 24 (89%) of 27 patients with GIST responded or had stable disease.4 Similarly, in the US B2222 study, which compared 400-mg and 600-mg imatinib doses, 81.6% of patients achieved partial response or prolonged stable disease.5 However, primary imatinib resistance was observed in all trials—11% in both EORTC studies, and 13.6% in study B2222. Of these patients, one in the EORTC phase I study and three in B2222 had disease stabilization or better after an increase in the imatinib dosage.3,5 The long-term follow-up on study B2222 was recently published in Journal of Clinical Oncology, and it indicated that the overall objective remission rate had improved with time to 68.1%, that the median duration of response was 29 months, and that neither response rate nor duration were different between the two doses.6 To explore additionally the impact of imatinib dosage, two phase III trials were performed that compared the standard 400-mg dose (which represented the dose established as efficacious in chronic myeloid leukemia trials) with the 800-mg MTD from the EORTC study. Both study 62005, performed in Europe and Australia, and the North American study S0033 allowed patients initially treated with imatinib 400 mg daily who failed to respond, or who progressed after an initial response, to cross over to 800 mg. This resulted in disease stabilization in 28% to 29% of patients, some of whom (18% in the EORTC trial) were still receiving treatment a year later.2,7
The relationship between GIST and activating mutations in KIT was first reported by Hirota et al.8 In addition to the commonest mutation in exon 11, which codes for the juxtamembrane domain, mutations in exons 9 and 12 were also described.9 Heinrich et al10 also reported activating mutations in the platelet-derived growth factor receptor It was reported by Verweij et al1 that patients treated with imatinib 800 mg had a superior PFS. At a median follow-up of 760 days, 56% of patients in the 400-mg arm had progressed compared with 50% in the 800-mg arm, which provided a hazard ratio for progression of 0.83 (P = 0.026) in favor of the higher dose. The higher dose was associated with an increased likelihood of grades 3 and 4 adverse effects and a greater incidence of dose reductions for toxicity. The genotype study referred to earlier subsequently showed this difference in PFS for the whole population to be caused by the improved response rate and PFS of patients with KIT exon 9 mutations who were treated with imatinib 800 mg daily compared with 400 mg (P = .0013); however, their PFS rate was still inferior to that of patients who had exon 11 mutations.12 No detectable difference according to dose was observed in the patients with exon 11 mutations. Surprisingly, the North American studies B2222 and S0033 did not support this finding; neither showed a difference in PFS or overall survival (OS) between the two imatinib dose groups.2,6,13 It is possible that this was due to the smaller dose difference in B2222 and the larger power of the EORTC trial to demonstrate a much smaller (10%) difference in PFS compared with S0033. In the detailed study of the impact of genotype on prognosis in study S0033, that was reported in this issue of JCO by Heinrich et al,13 there were only 31 patients who had CD117-positive KIT exon 9–mutant tumors compared with 58 in the report by Debiec-Rychter et al.12 This is the likely explanation of the fact that in spite of time to progression (TTP) being twice as long with the larger 800-mg dose (ie, 18 months compared with 9.4 months for the 400-mg arm), this was not statistically significant.13 However, the larger dose was more likely to result in an objective response; complete responses (CRs) and partial responses (PRs) were 17% for imatinib 400 mg and 67% for imatinib 800 mg. No differences were seen in any parameter according to dose in exon 11–mutant and wild-type groups. The previously reported impact of genotype on prognosis was again confirmed. The response rate was significantly higher for the KIT exon 11–mutant genotype (n = 283; CR/PR, 71.7%) than for the exon 9–mutant (n = 32; CR/PR, 44.4%) or wild-type (n = 67; CR/PR, 44.6%) genotypes. Median TTP results were 24.7, 16.7, and 12.8 months, respectively. At the time of publication, OS data were not available for the 62005 genotype study. However, striking differences in OS are reported by Heinrich et al,13 and they reflect the differences in TTP. The median OS was 60 months for patients with GIST containing exon 11–mutant KIT who were treated with imatinib 400 mg. This has not yet been reached in the 800-mg arm, whereas OS was significantly reduced at 38.6 and 38.4 months for the imatinib 400 mg and 800 mg exon 9–mutant KIT groups respectively, and it was 49.0 and 39.5 months for the imatinib 400 mg and 800 mg wild-type GIST groups, respectively. Despite the lack of a statistically significant difference in TTP for exon 9–mutant tumors according to dose in S0033, a meta-analysis of the combined data on 1,640 patients from both trials, which was presented at the Annual Meeting of the American Society of Clinical Oncology in 2007 by Van Glabbeke et al,14 showed that PFS remained statistically superior for patients with exon 9–mutant disease who were treated with imatinib 800 mg compared with 400 mg (HR, 0.58; P = .017). In addition to the relative imatinib resistance associated with exon 9 mutations, certain other mutations, such as the D842V mutation in PDGFRA—the commonest primary activating mutation in this gene—are associated with 10- to 20-fold resistance in vitro and with clinical resistance to imatinib.11,12 Additional information is provided in the study by Heinrich et al13 on CD117-negative patients, of which 10 were confirmed to have GIST on pathology review. Eight of these had mutations; six were in KIT, and two were in PDGFRA. Although TTP was similar to that of CD117-positive patients, median OS was significantly worse; it was 25.8 months versus 57.1 months for the CD117-positive group as a whole. However, the exon 11–mutant, CD117-negative patients had similar TTP and OS, so perhaps this just reflects the small number of patients, the fact that the two 2 PDGFRA mutations were unfavorable (in exon 18), and that two patients had wild-type disease; none of these patients responded. In addition to genotype, other possible prognostic factors were examined; of them, male sex, advanced age, poor performance status, high granulocyte count (absolute neutrophils count), and low hemoglobin had a significant adverse impact on OS. Of these, only male sex and poor performance status were significant correlates of diminished TTP in multivariate analysis. Van Glabbeke et al15 had previously reported initial resistance to imatinib in patients with GIST that were associated with high granulocyte count and low hemoglobin. Late resistance, defined as progression beyond 3 months, also was associated with high baseline granulocyte count, large tumor size, nongastric primary, and allocation to imatinib 400 mg daily. The clear association between high granulocyte count and poor prognosis identified in both studies is intriguing, but it currently remains an enigma. The commonest mechanism of acquired imatinib resistance appears to be the development of secondary mutations in KIT or PDGFRA.16 The evolution of acquired resistance, which may be polyclonal, may present as nodular changes in tumor density on computerized tomography (CT).17 The requirement for alternative agents to treat intrinsic and acquired imatinib-resistant GIST resulted in the testing of a number of candidate tyrosine kinase inhibitors, including PKC412, dasatinib, motesinib (AMG706) and sunitinib (SU11248), for activity against imatinib-resistant GIST in vitro and in vivo. Some of these subsequently entered clinical trials.18-21 Of these, sunitinib, an inhibitor not only of KIT, PDGFRA, and PDGFRB, but also of vascular endothelial growth factor receptors (VEGFRs) and FMS-like tyrosine kinase 3, showed activity against imatinib-refractory GIST in a phase I/II clinical trial.22 A subsequent randomized, placebo-controlled, phase III study demonstrated a highly significant benefit in PFS, which led to the licensing of sunitinib for this indication.23 A preliminary report of the relationship between primary and secondary mutations and sunitinib activity indicated that patients who had primary KIT exon 9–mutant or wild-type GIST were more likely to benefit clinically (defined as PR or stable disease > 6 months) and to have superior PFS compared with those who had primary exon 11–mutant tumors.24 Secondary mutations were also reported to be more common in patients who had primary exon 11–mutant disease; some, but not all, of the secondary mutations were sensitive to sunitinib according to in vitro data. The article in this issue from Heinrich et al25 now provides us with a detailed insight into the impact of genotype on primary and secondary resistance to imatinib and the precise role of sunitinib in this situation. The study reports the detailed genotype analysis of 78 patients who took part in the phase I/II study of sunitinib in the treatment of imatinib-refractory GIST. The key findings, as previously reported,24 are that responses to sunitinib were more common in patients who had primary mutations in KIT exon 9 compared with exon 11 (37% v 5%; P = .002). Response duration was also longer in the exon 9 –mutant and wild-type groups, which had median PFS rates of 19.4 months and 19.0 months, respectively, compared with only 5.1 months for patients who had exon 11–mutant tumors. A similar difference was also seen in OS. Responses were not seen in patients who had PDGFRA mutations. Secondary mutations were studied also. These clustered in exons 13 and 14, which encode the receptor ATP-binding pocket, and in exons 17 and 18, which encode the activation loop. Biopsies were generally limited to one per patient, but one patient had different secondary mutations in different lesions. Such polyclonality may be quite a common phenomenon. No secondary mutations were found in the eight patient samples that lacked primary KIT or PDGFRA mutations. Secondary mutations had a major impact on sunitinib activity. The median PFS was significantly longer for patients who had secondary mutations in exons 13 or 14 than for those who had exon 17 or 18 mutations (7.8 months compared with 2.3 months; P = .0157), a difference which was also associated with improvement in OS. The molecular basis for the observed differences in response was additionally studied by using a variety of in vitro techniques that involved KIT or PDGFRA mutants transiently expressed in Chinese hamster ovary cells or in GIST cell lines derived from imatinib-resistant tumors that expressed different mutations. Receptor inhibition was measured by studying the impact of imatinib and sunitinib on autophosphorylation by Western blotting; in the case of wild-type genotype, the receptors were ligand activated. Sunitinib inhibited ligand-activated, wild-type KIT and the KIT exon 11 V560D and exon 9 AY insertion mutants. In all three instances, the 50% inhibitory concentration was less than 100 nmol/L. By comparison, the 50% inhibitory concentrations for imatinib were 1,000 nmol/L, 100 nmol/L, and 1,000 nmol/L for wild-type tumors, V560D mutants, and exon 9 AY mutants, respectively. Clearly, this confirms the clinical superiority of sunitinib compared with imatinib in the treatment of wild-type or exon 9–mutant disease. Sunitinib also potently inhibited double mutants in KIT exons 11 + 13 or 11 + 14, which have secondary mutations in the ATP binding pocket against which imatinib was ineffective. However, sunitib was inactive against those in the activation loop (exons 17 and 18), as was imatinib. The commonest misconception regarding the activity of sunitinib is that it is relatively ineffective against KIT exon 11–mutant GIST. The in vitro data do not support this view. The likely explanation is that acquired secondary mutations are more likely to develop after prolonged exposure to imatinib in responsive KIT exon 11–mutant disease compared with wild-type and exon 9–mutant disease that is intrinsically resistant. This is what was observed in the study by Heinrich et al;25 secondary mutations occurred much more commonly in patients who had GISTs with primary KIT exon 11 mutations than in those with exon 9 mutations (73% v 19%; P = .0003). Clinical experience with imatinib in patients who have resistant disease suggests that some patients progress more rapidly when the drug is discontinued, despite having radiologic progressive disease. One explanation is that resistance is polyclonal, as discussed earlier, and that not all tumor cells possess secondary mutations that confer resistance. Another possible explanation is suggested by data from the report by Heinrich et al:25 GIST48 cells that are homozygous for the activating KIT exon 11 V560D mutation and heterozygous for the exon 17 D820A mutation, although effectively resistant to both sunitinib and imatinib, were partially inhibited by low doses (100 nmol/L) of either agent, perhaps because of inhibition of V560D homodimers. What remains unclear from the detailed molecular studies reported by Heinrich et al25 is the extent to which the potent antiangiogenic properties of sunitinib contribute to its activity against imatinib-resistant GIST, given that imatinib lacks vascular endothelial growth factor receptor inhibitory activity. In addition, studies that compare imatinib and sunitinib as first-line therapy are required to answer the question of whether the two drugs are truly different in their activity against primary exon 11–mutant GIST or whether sunitinib is more effective than imatinib 800 mg against exon 9–mutant tumors. A word of caution is that these data on sunitinib were derived from only 78 patients. We know by comparing the preliminary data from an examination of the impact of genotype on the PFS of 127 patients who were treated with imatinib,11 with subsequent data from larger patient populations, that the details may vary even though the basic message is unchanged.12,13 Until these findings have been confirmed in a larger population, it would be unwise to use them as a basis for determining the choice of treatment. The problem for those who treat GIST is how to use genotype data in the day-to-day management of patients who have imatinib-resistant disease. It is clearly important to know the primary genotype for prognosis and possibly for the choice of initial imatinib dosage. Knowledge of secondary mutations in those patients with imatinib-refractory disease who do not have wild-type or KIT exon 9–mutant disease may also be valuable in determining whether sunitinib will be useful or whether alternative, more experimental, approaches, such as HSP90, inhibition should be explored.26,27 If polyclonal resistance is truly common, this represents a major challenge.28 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Ian R. Judson, Pfizer (C), Novartis (C) Stock Ownership: None Honoraria: Ian R. Judson, Pfizer, Novartis Research Funding: Ian R. Judson, Pfizer Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on October 27, 2008 REFERENCES 1. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004[CrossRef][Medline] 2. Blanke CD, Rankin C, Demetri GD, et al: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626-632, 2008 3. van Oosterom AT, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358:1421-1423, 2001[CrossRef][Medline] 4. Verweij J, van Oosterom A, Blay JY, et al: Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 39:2006-2011, 2003[CrossRef][Medline] 5. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002 6. Blanke CD, Demetri GD, von Mehren M, et al: Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26:620-625, 2008 7. Zalcberg JR, Verweij J, Casali PG, et al: Outcome of patients with advanced gastrointestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751-1757, 2005[CrossRef][Medline] 8. Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations of c-KIT in human gastrointestinal stromal tumors. Science 279:577-580, 1998 9. Lux ML, Rubin BP, Biase TL, et al: KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 156:791-795, 2000 10. Heinrich MC, Corless CL, Duensing A, et al: PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708-710, 2003 11. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003 12. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006[CrossRef][Medline] 13. Heinrich, MC, Owzar K, Corless L, et al: Correlation of kinase genotype and clinical outcome in the North American intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol doi;10.1200/JCO.2008.17.4284 14. Van Glabbeke M, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumor (GIST): A meta-analysis based on 1,640 patients. J Clin Oncol 25;546s, 2007 (suppl; abstr 10004) 15. Van Glabbeke M, Verweij J, Casali PG, et al: Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: A European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 23:5795-5804, 2005 16. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 22:3813-3825, 2004 17. Desai J, Shankar S, Heinrich MC, et al: Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 13:5398-5405, 2007 18. Growney JD, Clark JJ, Adelsperger J, et al: Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood 106:721-724, 2005 19. Schittenhelm MM, Shiraga S, Schroeder A, et al: Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 66:473-481, 2006 20. Polverino A, Coxon A, Starnes C, et al: AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and KIT receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66:8715-8721, 2006 21. Faivre S, Delbaldo C, Vera K, et al: Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25-35, 2006 22. Maki RG, Fletcher JA, Heinrich MC, et al: Results from a continuation trial of SU11248 in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol 23;818s, 2005 (suppl; abstr 9011) 23. Demetri GD, van Oosterom AT, Garrett CR, et al: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 368:1329-1338, 2006[Medline] 24. Heinrich MC, Maki RG, Corless CL, et al: Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correleates with KIT and PDGFRA mutation status. J Clin Oncol 24;520s, 2006 (suppl; abstr 9502) 25. Heinrich MC, Maki RG, Corless CL, et al: Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol doi:10.1200/JCO.2007.15.7461 26. von Mehren M: Beyond imatinib: Second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors. Clin Colorectal Cancer 6:S30-S34, 2006 (suppl 1)[Medline] 27. Bauer S, Yu LK, Demetri GD, et al: Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 66:9153-9161, 2006 28. Heinrich MC, Corless CL, Blanke CD, et al: Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764-4774, 2006 Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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gene (PDGFRA) and found that PDGFRA and KIT mutations appeared to be mutually exclusive. In a study of the genotype of 127 patients in study B2222, Heinrich et al
